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Nodular fasciitis: USP6-associated neoplasia through multiple pathways

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Review | DOI: https://doi.org/10.31579/2640-1053/100

Nodular fasciitis: USP6-associated neoplasia through multiple pathways

  • Kazumi Fujioka 1

Department of Radiology, Nihon University School of Medicine, 30-1 Ohyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan. 

*Corresponding Author: Kazumi Fujioka, MD. PhD. Department of Radiology, Nihon University School of Medicine, 30-1 Ohyaguchi-kamicho, Itabashi-ku, Tokyo 173-8610, Japan.

Citation: Kazumi Fujioka. (2021). Nodular fasciitis: USP6-associated neoplasia through multiple pathways. J Cancer Research and Cellular Therapeutics. 5(5); Doi: 10.31579/2640-1053/100

Copyright: © 2021 Kazumi Fujioka, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Received: 09 October 2021 | Accepted: 25 October 2021 | Published: 29 October 2021

Keywords: nodular fasciitis; self-limited nature; USP6-associated neoplasia; high-resolution ultrasonography; USP6- related genes

Abstract

Even though nodular fasciitis (NF) is benign and self-limited nature, the presentations of clinical, ultrasonographic, and pathological features have been described as mimicking sarcoma. Erickson-Johnson et al. suggested that ubiquitin-specific protease 6 (USP6) transcriptional upregulation may be the driving force behind the high proliferative activity and growth of NF. When the lesion showed the proliferative findings of the margin on both ultrasonography (US) and pathology, accompanied by clinically rapid growth, self-limited and/or regress course, NF could be strongly suggested as previously described. In this article, the author reviews the current knowledge of NF as USP6-associated neoplasia and also describes the therapeutic strategy in NF. In addition to the presentations of clinical, ulrtrasonographic, and pathological appearances of NF, the evaluation of percentage of USP6 break-apart FISH signals reflecting lifetime and mitotic counts in NF may be a potential procedure for accurate diagnosis in particularly young NF. It is putative that the inhibition of USP6-related genes might be the potential therapeutic strategies for the extremely rare malignant nodular fasciitis.  

Introduction

Erickson-Johnson et al. [1] suggested that USP6 transcriptional upregulation may be the driving force behind the high proliferative activity and growth and the consistent involutional nature of NF. The author previously reported the case series of NF and strongly suggested that proliferative findings of the margin of the nodule on US and pathological features are caused by the driving force of USP6 transcriptional upregulation behind the high proliferative activity and growth of NF from an established cytogenetic nature. In this article, the current knowledge of NF as USP6-related neoplasia will be reviewed. The author also describes the therapeutic strategy in USP6-associated neoplasia such as aneurysmal bone cyst (ABC) and NF. 

Transient neoplastic nature in nodular fasciitis 

NF is a benign soft tissue tumor of fibroblastic/myofibroblastic differentiation that was first described in 1955 by Konwaler et al. [2]. While, Goodlad et al. [3] documented the first case of dermal nodular fasciitis (DNF) in 1990. The author previously has reported a common subcutaneous NF [4] and a rare intradermal type [5]. Though this entity of the intradermal type have very rarely occurred, De Feraudy et al. [6] have studied intradermal nodular fasciitis as a rare lesion analyzed in a series of 24 cases, and recently the lesion involved both the dermis and subcutis as a superficial nodular fasciitis [7] and a dermally located lesion [8] have been reported in the dermatologic field. NF presents most typically in the upper extremities, the trunk, and the head and neck. It usually presents between the ages of 20 and 40 years, often with tenderness [4]. The subcutaneous, fascial, intramuscular, and rarely intradermal type have been found [5]. NF shows a peculiar clinical behavior characterized by rapid, self-limited growth and spontaneous regression after a few weeks. Pathologically, NF typically featured uniform spindled cells arranged in irregularity intersecting short fascicles, and occasional storiform patterns. The cells contained plump, spindled to stellate nuclei with fine to open chromatin and small nucleoli. The background stroma ranged from myxoid to collagenous [4]. The characteristic tissue culture-like, feathery myxoid appearance was present at least focally [9]. Immunohistochemically, spindle cells in NF contain vimentin, muscle-specific action, and smooth muscle-specific actin [10], whereas it is known that NF is negative for several markers such as desmin, keratin, or S-100 protein in contrast to sarcoma [11]. Due to the aggressive clinical presentation, malignant ultrasonograpic appearances, and the histopathology with its high cellularity and high mitotic activity, NF can be misdiagnosed as a malignant soft tissue tumor, often leading to unnecessarily aggressive therapy [12]. 

High-resolution ultrasonography appearances in nodular fasciitis

Recently, dermatologic ultrasound imaging has been growing because of the development of high-resolution multifrequency transducers and multichannel color Doppler machines [13]. In dermatology, a 15 MHz is the minimum frequency recommended for performing dermatologic examination by the international working group or DERMUS (Dermatologic Ultrasound) [13, 14]. The author has reported a subcutaneous NF representing compressed fascia using both high-resolution ultrasonography (US) and magnetic resonance imaging (MRI) appearances [4] and a rare case of intradermal type showing the primarily in the dermis accompanied by the dilatation and proliferation of the vessels using high-resolution color Doppler ultrasound [5], it is known that high- resolution US can clearly represent the location of the dermis and subcutaneous, association of the fascia, and the presence of dilation and proliferation of the vessels. The author usually performs US studies for dermatologic fields with a high-resolution, broad-band (5MHz-18MHz) linear transducer and described several studies [4, 5, 15-29]. 

Presentations of clinical, ultrasonographic, and pathological features of nodular fasciitis from an established cytogenetic viewpoint

Even though NF is benign and self-limited, the clinical, ultrasonographic and pathological presentations have been described as mimicking sarcoma. Erickson-Johnson et al. [1] suggested that USP6 transcriptional upregulation may be the driving force behind the high proliferative activity and growth of NF. The author previously reported that irregular or lobular margin on US and poorly defined margin on histology is attributed to the cytogenetic nature of NF [15]. Furthermore, the research results strongly suggested that proliferative findings the margin of the nodule on US and pathological features are caused by the driving force of USP6 transcriptional upregulation behind the high proliferative activity and growth of NF from an established cytogenetic nature [17]. When the lesion showed the proliferative findings of the margin on both US and pathology, accompanied with clinically rapid growth, self-limited and/or regress course, NF could be strongly suggested as previously described [17]. 

Fusion patterns of USP6 in nodular fasciitis

A clear relationship between NF and a recurrent genetic abnormality had been established in FISH analysis [1, 9, 30-33]. Genomic rearrangements of the USP6 locus were found in 92% of NF. Rapid amplification of 5’-cDNA ends identified MYH9 as the transcription partner. The fusion of the MYH9 promoter region to the entire coding region of USP6 was shown using RT-PCR and direct sequencing [1]. The result indicated that the MYH9-USP6 fusion was demonstrated in 12 of 16 (75%) [1]. USP6 oncogenes was also detected in aneurysmal bone cyst (ABC) [34, 35], suggesting that these histological manifestations in ABC and NF may have a common pathogenic denominator mediated by USP6 transcription upregulation [1]. Regarding ABC, Ye et al. reported the USP6-induced expression of matrix metalloproteases through activation of NF-κB, a transcription factor with a key role in inflammation and proliferation [36]. Oliveira et al. suggested that ABC and NF reside in the same biologic spectrum, namely USP6-induced tumors [37]. Shin et al. reported that FISH analysis for USP6 had a sensitivity of 86% and specificity of 100% for a diagnosis of NF [9]. While, Erber et al. reported that the sensitivity and specificity of USP6 FISH for NF was 74.4% and 100%, respectively [31]. These studies indicate a clear association between NF and a recurrent genetic abnormalities in FISH analysis. 

 MYH9 is located on chromosome 22q12.3-q13 [1] and it is the most frequent fusion partner [1, 33]. RRBP1, CALU, CTNNB1, MIR22HG, SPARC, THBS2, and COL6A2 as less frequent gene partners has been detected [32]. These studies demonstrated the neoplastic nature of NF and USP6-associated neoplasia [32]. SEC31A, EIF5A, COL1A1, COL1A2, PAFAH1B1, SERP1NH1, COL3A1 have been also identified [38-45]. Regarding EIF5A, the USP6 gene rearrangement was shown by using FISH and a subsequent analysis demonstrated a novel EIF5A-USP6 gene fusion by means of the Archer fusionPlex Sarcoma kit [8]. They mentioned that the genesis of NF is also caused by Wnt signaling pathway which is the essential target of USP6 [8]. PPP6R3-USP6 fusion has been shown in two cases of NF accompanied with malignant manifestation [44, 45].Regarding the cutaneous NF, Kumar et al. [30] have described the presence of the USP6 rearrangement and MYH9-USP6 fusion, suggesting that the similar cytogenetic nature has been revealed both in subcutaneous NF and intradermal type. 

Nodular fasciitis as USP6-associated neoplasia through pathway 

Due to the identification of structural similar USP6 fusion gene in both ABC and NF, it is suggested that these diseases are clonal neoplasia that may have the same biological spectrum [37]. Myositis ossificans (MO) and fibro-osseous pseudotumor of digits (FOPD) also show the identification of USP6 gene fusion, indicating that these lesions may present the same entity. It is known that multiple fusion patterns of USP6 lead to transcriptional activation of USP6 [46, 47]. 

 Regarding the signaling pathways, USP6 induces several signal pathways including NFκB, Wnt/β-catenin, and JAK-1-STAT3 during tumorigenesis [46, 48, 49]. The important role of Jak1-STAT3 signaling in USP-6-related tumorigenesis has been reported [48], whereas Madan et al. [49] described that USP6 oncogene promotes Wnt signaling by deubiquitylating Frizzleds. Recently, Li et al. [50] reported that c-Jun is a novel substrate of USP6 and might serves as an essential role of NF.

 Regarding Wnt signaling pathway [49], it has been noted that chromosomal translocations of NF cause USP6 overexpression, that in turn lead to transcriptional activation of the Wnt/β-catenin pathway. Inhibition of Wnt signaling pathway significantly attenuated the growth of USP6-driven xenograft tumors, suggesting that Wnt signaling is an essential target of USP6 in tumorigenesis of NF. The study by Madan et al. [49] revealed a new mechanism for pathological Wnt pathway activation in NF and ABC and suggested a novel treatment method to modulate Wnt signaling. With respect to the Jak1-STAT3 signal, Quick et al. [48] showed that the Jak1-STAT3 signals are potential effectors of the USP6-TRE17 oncogene in the tumorigenesis of ABC and NF. They showed that USP6 activates Jak1-STAT3 pathway by deubiquitinating Jak-1, resulting in the stabilization and STAT3 activation. It has been suggested that the tumorigenic activity of USP6 was decreased by a JAK family inhibitor, or by CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-mediated deletion of JAK1 or STAT3 [48]. It has been suggested that studies demonstrating the downstream effects of USP6 may contribute to the therapeutic strategy in patients with ABC and NF [50]. The novel genes, namely the Frizzled and JAK1 genes were recently demonstrated as USP6 substrates [48, 49]. While, Li et al. [50] described the transcription factor c-Jun as a novel substrate of USP6. It has been reported that USP6 stabilized the c-Jun protein and potentiated c-Jun-dependent downstream signaling and cell invasion. They suggested that the interaction between USP6 and c-Jun might be important in patients with NF. It is known that USP6 has been shown to have potential roles in ABC and NF. Therefore they also suggest that the inhibition of c-Jun and other USP6-associated genes including JAK1 and Frizzled genes would produce the benefit in the patients with ABC and NF. The author suggests that the inhibition of c-Jun and other USP-related genes may be the potential therapeutic strategies for recurrent and/or inoperable ABC. Whereas the most of NF is benign, self-limited process including high proliferative growth activity and regress nature. Extremely rare malignant behavior of NF [44, 45] shown by USP6-PPP6R3 gene fusion has been reported. Based on the evidence, the author also suggests that the inhibition of USP6-related genes might be essential therapeutics in malignant behavior type of NF.       

Self-limited nature of NF from USP6-FISH (%) viewpoint

 The report [51] indicated that young NF defined as preoperative duration <1>3 months, suggesting that the result may demonstrate the connection with the self-limited nature of NF. The result indicated that in old NF, the percentage of USP6 break-apart FISH signals can be as low as 14-27%. It is putative that USP6 break-apart FISH signals reflect the growth activity and regress nature in NF. In addition to the presentations of clinical, ulrtrasonographic, and pathological appearances, the evaluation of percentage of USP6 break-apart FISH signals may be a potential procedure for diagnosis in young NF [17, 51]. In old NF, the author suggests that accurate diagnosis should be comprehensively made by the presentation of clinical, ultra sonographic, pathological, and cytogenetic features. The result showed a strong inverse relationship between the lifetime and percentage of USP6 break-apart signals and a strong positive association between USP6 break-apart signals and mitotic counts [51]. Based on the evidence, the author suggests that NF has the self-limited behavior so-called the proliferative activity and regression nature. It has been known that USP6 activation by promoter-swapping is characteristic feature accompanied with involvement of JAK-1/STAT1/STAT3 pathways leading to stabilization of the JUN protein [51]. In their research, the mRNA level of USP6, TRAIL, IFN-beta, JAK1, STAT1, STAT3, JUN, and CDKN2A as the pathways of the tumorigenesis of NF was evaluated using qRT-PCR, resulting in the significantly negative correlations between USP6-FISH and JAK1 and between USP6-FISH and STAT1. They also described that the role of the JAK-1/STAT1/STAT3 pathway is “active” during the whole lifetime of NF. While, it has been also suggested that cellular senescence through CDKN2A/p16 could be responsible for self-limited nature and a negative feedback mechanism that USP6 induces TRAIL-mediated apoptosis was revealed [52, 53]. They described that in young NF, the nuclear localization of TRAIL was shown and in old type, the dominant membraneous-cytoplasmic TRAIL positivity was represented [51]. 

Conclusion

In addition to the presentation of clinical, ulrtrasonographic, and pathological appearances, the evaluation of percentage of USP6 break-apart FISH signals reflecting lifetime and mitotic counts in nodular fasciitis may be a potential procedure for accurate diagnosis in particularly young nodular fasciitis. 

It is putative that the inhibition of USP6-related genes might be the potential therapeutic strategies for recurrent and/or inoperable aneurysmal bone cyst and extremely rare malignant nodular fasciitis. 

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We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.

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Layla Shojaie

The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.

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Sing-yung Wu

Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.

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Orlando Villarreal

Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.

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Katarzyna Byczkowska

Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.

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Anthony Kodzo-Grey Venyo

Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.

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Pedro Marques Gomes

Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.

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Bernard Terkimbi Utoo

This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.

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Prof Sherif W Mansour

Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.

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Hao Jiang

As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.

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Dr Shiming Tang

Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.

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Raed Mualem

International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.

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Andreas Filippaios

Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.

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Dr Suramya Dhamija

Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.

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Bruno Chauffert

I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!

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Baheci Selen

"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".

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Jesus Simal-Gandara

I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.

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Douglas Miyazaki

We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.

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Dr Griffith

I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.

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Dr Tong Ming Liu

I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.

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Husain Taha Radhi

I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.

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S Munshi

Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.

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Tania Munoz

“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.

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George Varvatsoulias

Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.

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Rui Tao

Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.

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Khurram Arshad